DESCRIPTION (from applicant's abstract): The major aims of this proposal are all focused on the serotonin 5-HT2A receptor, which is now being seen as a critical site for normal cognitive function and as a target for a typical antipsychotic agents. In the first aim, the PI will study how the oxygen substitution patterns in phenethylamine type 5-HT2A agonists affect orientation of the oxygen atom unshared electrons, which are clearly determinants of ligand recognition and activation. This information is critical to developing a 3D pharmacophore that can encompass all of the phenethylamine agonists possessing different substitution patterns. This aim will be accomplished by the synthesis of a variety of rigid analogues wherein the oxygen function is tethered into a ring of varying size, that forces the oxygen atom to adopt a particular conformation. Target molecules will be evaluated for both affinity and efficacy at the cloned rat 5-HT2a receptor, and will also be assessed for specificity at the cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors through a collaborative effort. The second aim is directed toward a study of the hypothesis that the late phases of LSD intoxication may resemble certain aspects of paranoid psychosis, a suggestion made by D.X. Freedman. In particular, we hypothesize that the initial 5-HT2A stimulatory effect of LSD sensitizes brain dopamine pathways to the effect of a potent dopaminergic metabolite, 13-hydroxy-LSD, which may accumulate during the action of LSD, and that this metabolite plays a key role in the psychopharmacology of the second temporal phase of LSD intoxication. These studies would have relevance to understanding possible roles of the 5-HT2A receptor in psychosis and schizophrenia. Major effort in this aim will be directed toward the synthesis and characterization of 13-hydroxy ergolines, using new approaches for construction of the ergoline nucleus. Drug discrimination studies will be employed to examine the nature of the LSD cue, as a function of time after administration, with a particular emphasis on the possibility that dopaminergic effects will predominate in the interoceptive cue at later times after LSD administration. The third aim is directed toward the synthesis of new, extremely potent (subnanomolar), agonist ligand for the 5-HT2 family of receptors. The initial target will be a molecule that can be tritiated to provide a radioligand with very high affinity and relatively high specific activity. A fourth aim is directed toward further examination of the effect of ring-fluorination on receptor selectivity of tryptamines. In particular, these studies are directed toward the preparation of new 5-HT1A receptor selective agonists.